Wheezing in acute respiratory
infections is a rule rather than exception. A
large proportion of children (up to 75%) having
‘pneumonia’ or ‘severe pneumonia’ as per WHO
definitions have associated wheezing. The current
strategies to diagnose and manage wheeze in the
community need to be updated, as audible wheeze is
present in only less than one-third of wheezy
children, and can not be relied upon solely. A
history of previous episodes of respiratory
distress has a high sensitivity to diagnose wheezy
disorders. In a significant proportion of
children, the respiratory rate comes back to
normal and the chest indrawing disappear after two
to three cycles of inhaled bronchodilator
medications. Operational research is needed to
evaluate the feasibility of including management
of wheezing in the community based ARI management
programs.

Keywords: Pneumonia, Respiratory tract
infections, Wheezing.

W

heezing is
associated with or contributory to a large
proportion of childhood acute respiratory infections
(ARI). For logistic reasons, the World Health
Organization (WHO) strategy for the control of ARI
has focused on the case management of pneumonia in
an attempt to reduce mortality. In the last two
decades, researchers from developing countries have
raised serious concerns over the applicability of
these guidelines in children having wheeze. The
diagnosis and management of wheeze has largely been
ignored resulting in overuse of antibiotics and
underuse of bronchodilator medications at the
community level. The operational aspects and
advocacy related to management of wheeze in ARI are
also missing from most health programs in developing
countries. To rationalize the antimicrobial and
bronchodilator prescription, it is essential to make
a reasonably accurate diagnosis of wheeze using
simple clinical tools.

How Common is Wheezing in ARI?

Wheezing is a musical sound
produced when the air flow from the lungs is
obstructed, due to contraction of the smooth muscles
surrounding the airways or swelling of the lining of
bronchioles. The main causes of wheezing in
under-five children are bronchial asthma,
bronchiolitis and pneumonia. Inhaled foreign bodies,
compression of the airways, from outside (as by
lymph nodes or a tumour), and pulmonary edema are
less common.

Wheezing is a very common symptom
or sign in under-five children, including infants.
Children with wheeze can have fast breathing or/and
lower chest indrawing, and are likely to be
categorized as pneumonia or severe pneumonia
according to the current ARI case management
guidelines. Hospital based studies from Delhi, India
have documented asthma to be more common diagnosis
than pneumonia in under-five children having the
symptoms of cough or difficult breathing(1-3). Using
the WHO/IMCI algorithms, there was a considerable
overdiagnosis of pneumonia because of inclusion of
cases of asthma and other respiratory ailments(1,2).
In a study enrolling children aged between six
months to five years, wheezing was found in 75% (150
out of 200) of the subjects presenting with signs of
fast breathing or lower chest indrawing(3). Asthma
was the predominant diagnosis in almost half of
these cases whereas pneumonia (with or without
wheezing) was the diagnosis in only one-third of
cases. In an Indian multicentric study designed for
comparing the efficacy of three day and five day
amoxicillin treatment in non-severe pneumonia,
wheezing was present in 13% of cases(4). The low
prevalence of wheezing in this study was because of
a two stage screening procedure resulting in
exclusion of children with recurrent respiratory
distress, and also those in whom ‘fast breathing’
disappeared after an initial course of
bronchodilators. In another recent multicentric
study enrolling more than 2000 under-five children
from rural primary health centers in India, wheezing
was documented in 22% of children having WHO defined
non-severe pneumonia, despite excluding cases with
recurrent respiratory distress(5). In children
having lower chest indrawing (categorized as severe
pneumonia as per WHO definition), the prevalence of
wheezing is even higher. In a recent multicentric
trial evaluating the efficacy of oral drugs in
treatment of severe pneumonia in children from
Pakistan(6), wheezing on auscultation was present in
76% of 2037 children with lower chest indrawing
despite excluding known asthmatics and those
responding to initial bronchodilators. The
prevalence of wheezing was much more in infants in
comparison to children aged more than one year (82%
vs. 65%).

From the foregoing, it is evident
that wheezing is present in majority of children
diagnosed as pneumonia or severe pneumonia, based on
the presence of fast breathing and chest indrawing,
respectively. Wheezing is common even in those
children who are not having recurrent episodes of
respiratory distress, and those who do not respond
to initial course of inhaled bronchodilator therapy.

Diagnosis of Wheeze in the
Community

The current WHO strategy for the
management of ARI relies heavily on standardized
case management for preventing pneumonia deaths. For
management of wheeze, the guidelines recommend
giving two cycles of rapid acting inhaled
bronchodilator at 15 minute intervals to children
with audible wheeze and fast breathing and/or lower
chest indrawing. Thus, the diagnosis of wheeze is
made by the health worker only if the child has
audible wheeze. Majority of children with wheezing
do not get identified by health workers using this
approach as only less than one-third of the children
with auscultatory wheeze have audible wheeze. In a
study from Delhi hospital, audible wheeze was
appreciated in only 44 of the 150 cases (29.3%) with
an auscultable wheeze(3). In a recent multicentric
study evaluating the role of antibiotics in
treatment of wheezy pneumonia in under-five Indian
children, audible wheeze was found in only 17% of
cases where it was present on auscultation(7). The
multicentric study enrolling children with severe
pneumonia from Pakistan also documented a prevalence
of audible wheeze in only 17% (261 out of 1545) of
the total wheezy children(6). The later two studies
had a lower prevalence of audible wheezing in
comparison to the earlier data from India(1,3) due
to exclusion of cases with known asthma and
recurrent episodes of respiratory distress. In
another multicentric study from Pakistan enrolling
all wheezy children, the prevalence of audible
wheeze was 37%(8).

As the present strategy of
relying on audible wheeze for institution of
bronchodilator therapy results in gross
underutilization of bronchodilators and
overprescription of antibiotics, attempts have been
made to refine the community based diagnosis of
wheezing. In an observational study from New Delhi,
India(1), the best predictor for asthma related
wheeze was two or more earlier similar episodes
(sensitivity 84%, specificity 84%) followed by
presence of fever (sensitivity 73% and specificity
84%). It was further suggested to include these
simple clinical features [history of: (i)
previous similar episode of cough and difficult
breathing, and (ii) fever] in the WHO case
management algorithm to significantly refine the
antibiotic and bronchodilator prescription. The
alternative algorithm represented a significant
improvement over the WHO algorithm, primarily by
restricting over-prescription of the antibiotics and
under-utilization of the bronchodilators. Another
option is to give therapeutic trial with inhaled
bronchodilators before assigning the diagnosis of
pneumonia or severe pneumonia in all children with
‘fast breathing’ or ‘chest indrawing.’ Among cases
of non-severe pneumonia and wheeze, the respiratory
rate is known to come back below age specific
cut-offs in 46%-62% children(7,8). The response rate
in children with lower chest indrawing is somewhat
lower(8). However, such an approach is likely to
result in considerable overuse of bronchodilator
drugs, and may even delay the timely management or
referral of children with non-wheezy illnesses,
especially in those with lower chest indrawing. The
best approach remains the appropriate diagnosis of
wheeze by skilled personnel using the stethoscope.
In settings with high prevalence of wheeze, the
possibility of training health workers in the use of
the stethoscope should be explored in order to
further rationalize the case management of children
presenting with cough or difficult breathing. The
first referral units need to be equipped for
managing wheezy disorders.

Treatment of Wheeze in Children with Acute
Respiratory Infections

WHO recommended case management
of children presenting with cough or difficult
breathing, is structured towards treatment as
pneumonia in preference to acute asthma. With
changing disease epidemiology and rapid
urbanization, the prevalence of wheezy disorders,
including asthma is increasing in all age groups.
Accurate diagnosis and early institution of
bronchodilator therapy is important to prevent
asthma related fatalities.

Antibiotics

Antibiotics have no role in
management of wheezing due to bronchial asthma. A
history of recurrent episodes of respiratory
distress in the past, and good response to initial
bronchodilator therapy have high specificity to
diagnose asthma in children presenting with ‘fast
breathing’ or ‘chest indrawing.’ It is worthwhile to
withhold antibiotic therapy in such situations,
resulting in a substantial reduction in prescription
of antibiotics.

Although asthma is the most
common cause, infections of the respiratory tract
are also well known causes of wheezing and acute
exacerbation of asthma in children. Viruses are the
most common cause of wheezing associated with
respiratory tract infections. Respiratory syncytial
virus (RSV) infections have long been recognized to
produce the first episode of wheezing in children,
some of whom go on to develop chronic asthma(9). The
risk of pneumonia or bronchiolitis caused by RSV is
highest among children aged less than 2 years with
the most severe disease occurring in infants aged 3
weeks to 3 months. The rhinovirus, adenovirus and
human bocaviruses are other viruses responsible for
wheezing in children hospitalized because of
respiratory infection(10). Antibiotics have no role
in treatment of bronchiolitis due to RSV
infection(11). Though most literature suggest
viruses as the predominant cause of respiratory
infection associated wheezing, there is some
evidence suggesting a high prevalence of wheezing
amongst children having pneumonia due to
Streptococcus pneumoniae and Haemophilus
influenzae, the two most common bacteria
responsible for pneumonia(12). Viral or bacterial
coinfection is also a common finding in young
children with pneumonia in developing
countries(12-14). Overall, clinical differentiation
of viral and bacterial etiology in under-five
children persisting to have wheeze after initial
bronchodilator therapy, is difficult in community
settings.

A multi-centric, double blind
randomized placebo-controlled trial was conducted in
outpatient departments of 8 referral hospitals in
India(7), to specifically assess whether children of
non-severe pneumonia with wheeze can be effectively
managed without antibiotics and to identify which
sub-group of cases do require antibiotics. Clinical
failures occurred in 201 out of 836 cases (24.0%) on
placebo and 166 out of 835 cases (19.9%) on
amoxicillin (risk difference 4.2% in favour of
antibiotic, 95% CI: 0.2 to 8.1). Clinical failure
was associated with placebo treatment (adjusted OR=
1.28, 95% CI: 1.01 to 1.62). The trial concluded
that treating children with non-severe pneumonia and
wheeze with a placebo is not equivalent to treatment
with oral amoxicillin. However, the difference in
failure rate between two groups was less than 5% in
both ‘per protocol analysis’ and ‘intention-to-treat
analysis.’

On the basis of available
evidence, it appears justified to continue the
practice of giving antibiotics to children who are
diagnosed in the community to be having wheeze
associated with pneumonia, and who do not respond to
initial bronchodilator therapy. The choice of
antimicrobial in such situation is similar to that
in other children with pneumonia.

Bronchodilator Medications

As there is substantial evidence
that wheeze is common in children fitting into the
criteria of either ‘pneumonia’ or ‘severe pneumonia’
as per WHO/IMCI guidelines, and also that these
signs are likely to disappear after two to three
cycles of inhaled bronchodilator therapy in about
one-third to half of the cases, this form of therapy
has a major role in management of children
presenting with cough or difficult breathing.
Inhaled beta-2 adrenergic drugs (salbutamol or
terbutaline) remain the mainstay of bronchodilator
therapy for treatment of wheeze. These drugs can be
given in young children by either nebulizer or
metered dose inhalers (MDI) along with spacer and
mask attachment. Delivery of bronchodilator
medications via a nebulizer driven by an electric
compressor or oxygen cylinder is an effective, safe
and well-established technique. However, need of
electricity to run the compressor, constraints in
availability of high flow oxygen cylinders, and high
cost of equipments limit the routine use of this
technique in most primary health care settings of
developing countries. Metered dose inhalers with
spacer devices may be the most appropriate method
for administering these medications to children in
these settings, due to their easy availability and
ease of administration. There is substantial
evidence showing the efficacy of such devices in
treatment of childhood asthma. The cost of
equipments can further be reduced by using
improvised home made spacer devices. A systematic
review(15) of six trials comparing efficacy of
commercial and home-made spacers in childhood asthma
did not demonstrate any significant difference
between the two delivery methods in terms of the
need for hospital admission (RR 1.00, 95% CI 0.63 to
1.59), change in oxygen saturation (SMD -0.03, 95%
CI -0.39 to 0.33), peak expiratory flow rate (SMD
0.04, 95% CI -0.72 to 0.80), clinical score (WMD
0.00, 95% CI -0.37 to 0.37), or need for additional
treatment (RR 1.18, 95% CI 0.84 to 1.65).

Despite high prevalence and
possibility of successful management using simple
tools and medications, published evidence regarding
management of wheeze in the community in a
developing country setting is severely lacking. The
subsequent clinical course of children who respond
to initial bronchodilator therapy, and are sent home
without antibiotics, is also a case of concern. A
multicentric study from Pakistan designed to study
the course and profile of under-five children
managed with 3 cycles of inhaled bronchodilator
therapy, documented that 15% and 38% of the
non-severe and severe pneumonia group, respectively
showed subsequent deterioration on follow up(8). No
family history of wheeze, fever (temperature
>100şF), and lower chest indrawing were identified
as predictors of subsequent deterioration. It is,
therefore, prudent to ensure adequate follow-up of
children diagnosed and managed in the community with
initial course of inhaled bronchodilators. The
issues related to safety and adherence to the
continuation of bronchodilator medications at home
also need to be addressed. The clinical outcome of
under-five children with wheeze has been shown to be
similar when treated with oral or inhaled salbutamol
at home after initial response to inhaled
bronchodilator therapy(16).

Epilogue

As wheezing is seen in majority
of under-five children who are otherwise diagnosed
as having ‘pneumonia’ or ‘severe pneumonia’ as per
WHO/IMCI definitions, the case management guidelines
for diagnosis of wheeze in children with ARI need to
be refined. A large proportion of these children can
be successfully managed without antibiotics, using
simple devices and medications. Health workers in
community need to develop skills in recognizing and
managing wheeze in order to successfully manage ARI,
and to rationalize antibiotic therapy. Health care
facilities managing children with ARI must be
equipped with facilities to diagnose and treat
wheezy children. Health programs involving
management of childhood ARI in developing countries
need to incorporate the diagnosis and management of
wheeze. Operational research is urgently required to
test the feasibility and utility of management of
wheeze by trained health workers in actual field
situations.

Contributors: The article was
conceived by PG and DS. DS searched the literature
and wrote the paper, which was edited by PG. Both
authors approved the final draft.